ALDH1A3

Chr 15AR

aldehyde dehydrogenase 1 family member A3

Also known as: ALDH1A6, ALDH6, MCOP8, RALDH3

NCBI Gene: 220 ENSG00000184254 UniProt: P47895 OMIM: 600463

The protein catalyzes the NAD-dependent oxidation of retinal to retinoic acid, which is critical for embryonic development of the eye and nasal region. Autosomal recessive mutations cause isolated microphthalmia type 8, affecting ocular development. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.511), consistent with its essential role in early embryonic eye formation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an aldehyde dehydrogenase enzyme that uses retinal as a substrate. Mutations in this gene have been associated with microphthalmia, isolated 8, and expression changes have also been detected in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microphthalmia, isolated 8MIM #615113

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Microphthalmia, isolated 8; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.51

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.141

Z-score 3.31

OE 0.26 (0.14–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.24Z-score

OE missense 0.64 (0.57–0.72)

192 obs / 301.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.51)

0≤0.351.4

Missense OE?0.64 (0.57–0.72)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 6 / 23.2Missense obs/exp: 192 / 301.2Syn Z: 0.07

Background carrier burden — how many people carry a rare variant somewhere in ALDH1A3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 87

652 rare PASS variants

Rare truncating (LoF)

1 in 2,500

81 rare PASS variants

Rare synonymous (reference)

1 in 99

356 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALDH1A3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 94	1 in 3,200
South Asian	~43k	1 in 82	1 in 370
Remaining (unassigned)	~30k	1 in 70	1 in 260
European (Finnish)	~27k	1 in 240	1 in 290
Admixed American	~22k	1 in 120	1 in 1,100
African / African American	~21k	1 in 83	1 in 500
East Asian	~20k	1 in 98	1 in 1,800
Ashkenazi Jewish	~13k	1 in 290	1 in 2,400
Middle Eastern	~2,884	1 in 83	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 13 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 13.? see exons ↓